Roles of Calcium Regulating MicroRNAs in Cardiac Ischemia-Reperfusion Injury

Abstract

Cardiac Ca2+ cycling and signaling are closely associated with cardiac function. Changes in cellular Ca2+ homeostasis may lead to aberrant cardiac rhythm and may play a critical role in the pathogenesis of cardiac diseases, due to their exacerbation of heart failure. MicroRNAs (miRNAs) play a key role in the regulation of gene expression at the post-transcriptional level and participate in regulating diverse biological processes. The emerging evidence indicates that the expression profiles of miRNAs vary among human diseases, including cardiovascular diseases. Cardiac Ca2+-handling and signaling proteins are also regulated by miRNAs. Given the relationship between cardiac Ca2+ homeostasis and signaling and miRNA, Ca2+-related miRNAs may serve as therapeutic targets during the treatment of heart failure. In this review, we summarize the knowledge currently available regarding the role of Ca2+ in cardiac function, as well as changes in Ca2+ cycling and homeostasis and the handling of these processes by miRNAs during cardiac ischemia-reperfusion injury.

Figure 1

Cardiac Ca²⁺-handling and Ca²⁺-mediated signaling. LTCC, L-type Ca²⁺ channel; NCX, Na⁺/Ca²⁺ exchanger; CaM, calmodulin; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; Cn, calcineurin; RyR2, ryanodine receptor type-2; SERCA2a, sarcoplasmic reticulum Ca²⁺-ATPase; SR, sarcoplasmic reticulum; PLB, phospholamban; CICR, Ca²⁺-induced Ca²⁺ release; MCU, mitochondrial Ca²⁺ uniporter; ANT, adenine nucleotide transporter; VDAC, voltage-dependent anion channel; TCA, tricarboxylic acid; OXPHOS, oxidative phosphorylation; HDAC, histone deacetylase; NFAT, nuclear factor of activated T-cells; MEF2, myocyte enhancer factor-2; P, phosphorylation.

Figure 2

Cardiac Ca²⁺ protein-regulated microRNA during ischemia-reperfusion injury. LTCC, L-type Ca²⁺ channel; NCX, Na⁺/Ca²⁺ exchanger; AnxA5, annexin A5; NHE, Na⁺/H⁺ exchanger; CaM, calmodulin; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; RyR2, ryanodine receptor type-2; SERCA2a, sarcoplasmic reticulum Ca²⁺-ATPase; SR, sarcoplasmic reticulum; PLB, phospholamban; CICR, Ca²⁺-induced Ca2+ release; MCU, mitochondrial Ca²⁺ uniporter; ROS, reactive oxygen species; CyP-D, cyclophilin D; mPTP, mitochondrial permeability transition pore; OXPHOS, oxidative phosphorylation; HDAC, histone deacetylase; P, phosphorylation.